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A REVIEW OF OCULAR FUNGAL INFECTIONS OTHER THAN KERATOMYCOSIS: THE GLOBAL AND INDIAN SCENARIO

Somnath Sarkar1, Tapas Kumar Bhattacharya2, Atanu Roy3, Kumarjyoti Ghosh4

1Associate Professor, Department of Ophthalmology, MGM Medical College & LSK Hospital, Bihar. 2Associate Professor, Department of Microbiology, MGM Medical College & LSK Hospital, Bihar. 3Professor and HOD, Department of Microbiology, MGM Medical College & LSK Hospital, Bihar. 4Assistant Professor, Department of Microbiology, MGM Medical College & LSK Hospital, Bihar.

ABSTRACT Fungal ocular infections are common in the developing countries having hot, humid climate and poor health educational status. Trauma with vegetable matter, indiscriminate use of steroid in over-the-counter topical preparations and poor penetrability of antifungal agents make these disease entities common and rather difficult to treat. Besides corneal infections by fungi (Keratomycosis), there are other ocular sites which are involved: eyelids, conjunctiva, uvea, vitreous, retina, orbit and ocular adnexa. Some of these infections may be life-threatening and/or may lead to blindness. This review summarises the clinical features of the ocular involvement, discusses the risk factors for the infections and also explains about therapeutic and preventive measures to combat the infections. It also gives an idea of the current global and Indian disease spectrum.

KEYWORDS Non-keratitic Ocular Infection, Exogenous Fungal Infection, Endogenous Fungal Infection, Systemic Antifungal Drugs, Topical Antifungal Treatment, Rhino-Orbito-Cerebral Fungal Infection, Fungal Endophthalmitis.

HOW TO CITE THIS ARTICLE: Sarkar S, Bhattacharya TK, Roy A, et al. A review of ocular fungal infections other than keratomycosis: the Global and Indian scenario. J. Evolution Med. Dent. Sci. 2016;5(49):3168-3172, DOI: 10.14260/jemds/2016/734

INTRODUCTION Pneumocystis In the 1980s systemic fungal infection has emerged as a major Moulds Jirovecii in HIV Patients cause of human disease mainly affecting hospitalised patients, Candida species species particularly post-surgical, those with serious underlying C. albicans, C. illness; immuno-compromised patients and patients treated in glabrata, C. A. fumigatus, A. Intensive Care Units. Indian studies and statistics also indicate parapsilosis, flavus, that the incidence of systemic fungal infection is on the rise C. tropicalis, C. A. niger, A. tereus and is associated with increased morbidity and mortality.(1) krusei, C. Fungal ocular infections are common in the developing guilliermondii Zygomycetes countries with hot humid climate. They are also the most (Mucormycetes) difficult infections to treat in view of the rather poor Cryptococcus (2) penetration of antifungal agents. Long-term use of neoformans antifungal agents also gives rise to various systemic toxicities. 70% to 90% cases 10% to 20% cases of Fungal corneal ulcers represent the majority of cases of of invasive invasive infection ocular fungal infections. Trauma with vegetable matter and infection indiscriminate use of over-the-counter topical steroid Table 1: Agents causing Opportunistic Fungal Infection preparations are the main causes of development of fungal corneal ulcers. (2) Candida infection is common in diabetics and The affections in the eye other than that of the cornea have in the immunosuppressed patients. However, it has been seen been discussed below. that fungal disease may affect the eyes elsewhere other than LIDS that of the cornea. The lids may be affected in diabetic or immunosuppressed

patients. In patients with poor personal hygiene, in patients with chronic epiphora and in patients with excessive facial sweating, fungal infections may occur. Pityriasis versicolor and may occur in these patients. Itching with white discoloration or lid oedema may occur. The diagnosis is

mainly clinical. Skin scrapings are examined after 10% to 20% Financial or Other, Competing Interest: None. Submission 27-04-2016, Peer Review 27-05-2016, potassium hydroxide mount under the compound microscope. Acceptance 02-06-2016, Published 20-06-2016. This clinches the diagnosis as fungal elements are seen. The Corresponding Author: treatment is mostly with clotrimazole cream. Levocetirizine Dr. Somnath Sarkar, may be given to control the itching. The patients must be given Satabdi Apartment, Flat-4, 333/D, Jessore Road, Kolkata-700089, proper health education regarding maintenance of personal P.O. Lake Town, West Bengal. hygiene. The systemic diseases such as diabetes mellitus must E-mail: [email protected] be controlled. If the lesions prove refractory to topical therapy, DOI: 10.14260/jemds/2016/734 oral azoles can be added.

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Conjunctiva Necrotising granulomatous conjunctivitis due to Although various fungi can often be recovered from the immitis requires aggressive debridement of the conjunctiva, fungal conjunctivitis can rarely be observed affected area and prolonged topical and oral clinically. Isolation of fungi from normal conjunctival sac fluconazole therapy. and are occurs in 6 to 25% of normal individuals. A seasonal increase treated with itraconazole. presents in isolation of fungi from the conjunctival sac is observed to with fleshy, friable, red pedunculated mass which must be occur. This is possibly due to airborne carriage of Candida. excised with adequate margin.(7) Medical treatment is of no seems to be endemic in the Indian value in these cases. subcontinent.(3-5) UVEA, Vitreous and Retina The Predisposing Factors are.(6) Fungi may cause uveitis, vitritis, retinitis, chorioretinitis and 1. Shared cosmetics. even endophthalmitis. All these disease entities may hamper 2. Chronic use of topical broad-spectrum antibiotics. vision to a significant extent, if not treated on time. 3. Prolonged use of oral or topical steroids. Presumed Ocular Syndrome (POHS) is a 4. Injury from vegetable matter. syndrome characterised by multiple scars in the choroid 5. Bathing in stagnant water. (Histo spots), neovascularization, peripapillary atrophy with a 6. Immuno-compromised patients. clear vitreous and aqueous. POHS affects young and middle aged adults and is a major cause of choroidal Common fungi causing conjunctivitis are: Candida neovascularisation in patients younger than fifty years. POHS albicans, Candida parapsilosis, , causes permanent loss of vision in many patients. It is Paracoccidioides brasiliensis, , associated with HLA-DR15 (A subtype of HLA-D2) and HLA- Blastomyces dermatitidis, Rhinosporidium seeberi, DQ6 haplotype.(10) While rare cases of fungal endophthalmitis , etc. have been seen in patients with disseminated histoplasmosis, the association of with POHS is Clinical Features presumptive and based primarily on epidemiologic grounds. These are: In the United States POHS is most prevalent in the Midwest, 1. Redness. which is a region endemic for histoplasmosis. A previous study 2. Itching. in 1972 found that 4.4% of people living in an endemic area, 3. Discharge. who had tested positive by a histoplasmin skin test had ocular 4. Irritation. histo spots.(11) Other support for histoplasma capsulatum as the aetiology is lacking. However, POHS has been found in There is chronic inflammation and scanty eye discharge. areas where H. capsulatum is absent such as the The conjunctiva is congested with oedema formation. Netherlands.(12) Laser photocoagulation and intravitreal Granulomas can be seen.(7) The discharge may be yellow or administration of anti-VEGF agents are the primary treatment green in colour. modalities. There is no indication for antifungal treatment. Candida conjunctivitis commonly occurs in newborn, school children and adults with the primary lesion being in Fungal Endophthalmitis oral mucosa or vagina. Conjunctival membrane or Endophthalmitis is an inflammatory process involving the pseudomembrane may occur. ocular cavity and adjacent structures. Infectious infection presents with catarrhal conjunctivitis, endophthalmitis is mainly caused by and bacteria. It is whereas Coccidioides immitis causes a severe necrotising increasingly being understood that virtually any granular conjunctivitis and sometimes follicular conjunctivitis. microorganism can cause an infection inside the eye, if the Blastomyces dermatitidis causes contiguous spread and inoculum is a very large one. The most common fungus, which follicular conjunctivitis. Sporothrix schenckii presents with can cause metastatic endophthalmitis is Candida spp., nodular conjunctivitis along with associated deep lesions and especially in the setting of active fungaemia. lymphadenopathy. Aspergillus niger causes chronic Based on the mode of entry of the fungus, the conjunctivitis with black conjunctival secretions.(8,9) endophthalmitis is divided into exogenous and endogenous Immunocompromised patients may experience a severe types. Exogenous infection occurs when the fungus is clinical course with granulomatous conjunctivitis or introduced into the human eye from the environment. necrotising conjunctivitis with scleral melting. The condition Endogenous endophthalmitis occurs when haematogenous may masquerade as squamous cell carcinoma, a typical spread of fungus occurs. papilloma or conjunctival granuloma.(9) Based on aetiological type of microorganism, the Biopsy and histopathology is the recommended diagnostic endophthalmitis can be bacterial type of infection or fungal procedure. Giemsa stain of conjunctival scrapings may type of infection. Exogenous infection occurs when the fungus demonstrate the presence of small intracellular or gains entry from outside. Endogenous endophthalmitis occurs extracellular yeasts. Specific culture or PCR has a more if the disease is caused by the entry of fungi through the blood diagnostic yield. stream (Haematogenous route). Topical antifungal agents may be used. These include Amongst the exogenous endophthalmitis, 70% are Amphotericin B (0.15%), Natamycin (5%), Fluconazole (2%) postoperative endophthalmitis, which may be an early or late and Ketoconazole (2%). Systemic antifungals may be used for onset. Penetrating ocular trauma accounts for 7-30% or cases. associated deep lesions. Early onset endophthalmitis due to fungus may occur within 2 to 7 days after surgery, but later onset is commoner.

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The value of culture of vitreous and aqueous samples in the The patients may be divided into two major categories by diagnosis of infectious endophthalmitis is well established. incidence and response to therapy. These two categories are Sometimes negative cultures are encountered resulting in a Candida endophthalmitis and mould endophthalmitis. In clinical dilemma over the cause of the inflammation. It is industrialized nations and cooler climates, Candida difficult clinically to differentiate between infectious endophthalmitis is commoner than mould endophthalmitis. endophthalmitis and other similar inflammatory conditions, The reverse is true in tropical countries. such as phacoanaphylactic uveitis and idiopathic Candida endophthalmitis is usually endogenous and postoperative inflammation. responds well to treatment, whereas mould endophthalmitis is almost always exogenous and successful therapy is Category of Common Causative uncommon. Endophthalmitis due to Cryptococcus and the Endophthalmitis Organism dimorphic fungi Histoplasma and is rare Postoperative Acute and almost always a result of disseminated disease. Delayed Candida spp. Endophthalmitis due to moulds is rare in western Filtering countries, but it is seen in tropical parts, e.g. Florida in USA

bleb where 6% of 278 endophthalmitis cases treated between 1996 Penicillium spp., and 2001 were due to Aspergillus and other moulds. spp., In tropical countries such as , fungal endophthalmitis Post-traumatic Fungal Acremonium spp., is a significant problem. Moulds accounted for 22% of 170 other filamentous fungi postoperative endophthalmitis cases in Northern India.(13) and Yeasts (C. albicans, 21% of 170 postoperative endophthalmitis cases in Southern Cryptococcus spp.), India.(14) Filamentous fungi Mould endophthalmitis is usually exogenous with most Endogenous Fungal (Aspergillus spp., cases occurring as an extension of fungal keratitis Acremonium, (Keratomycosis) after penetrating eye trauma or after eye Fusarium, injury.(15) in intravenous drug abusers and in Paecilomyces spp.) immunocompromised patients including organ transplant (16,17,18) Table 2: Fungal Aetiology of Endophthalmitis patients and patients with haematologic malignancies. Most of these immunocompromised patients have a focus of (16,17) Chronic endophthalmitis occurs late due to less virulent fungal infection elsewhere, usually the lungs. Mould organisms like fungi, S. epidermidis and P. acne. Fungal endophthalmitis developing after surgery usually presents endophthalmitis may also be caused by saprophytes or subacutely 2-6 weeks postoperatively. Aspergillus is the opportunistic pathogens (e.g., Cephalosporium, Candida, common cause of mould endophthalmitis causing 50% to 60% (14,19,18) Aspergillus or Penicillium). Bleb induced endophthalmitis of cases. Fusarium is another common cause of mould occurring after trabeculectomy operation is usually caused by endophthalmitis and most cases result from Fusarium (20) virulent bacteria. keratitis. Several cases occurred after a nationwide Endogenous endophthalmitis is typically caused by fungi, outbreak of Fusarium keratitis from 2004 to 2006 associated (21) e.g. Candida parapsilosis, C. krusei and C. stellatoidea. The next with a contact lens cleaning solution. causative fungus in order of occurrence is Aspergillus spp. of which Aspergillus fumigatus dominates, but A. flavus has also Chorioretinitis and Vitritis been found. Some other fungi like Sporothrix schenckii, Rarely, fungi such as Coccidioides spp., Blastomyces spp., , C. immitis and Mucor have been Aspergillus spp. and Cryptococcus neoformans may cause reported in isolated cases. chorioretinitis by haematogenous spread. Nocardia spp. can In the laboratory diagnosis of the causative agents of occasionally cause chorioretinitis. Candida spp. can cause infection, the vitreous is the most appropriate specimen. It is retinitis and vitritis in neonates. The risk factors are subjected to smear and staining and is also cultured in SDA and prematurity, low birth weight, sepsis, malnutrition and PDA media. treatment with broad-spectrum antibiotics. Opportunistic Culture of non-ocular specimens is very significant for the infections with , H. capsulatum, C. diagnosis of endogenous endophthalmitis. The first important neoformans may produce multifocal choroiditis in patients step is blood culture. Sputum culture is important in cases of who have Acquired Immunodeficiency Syndrome (AIDS). respiratory tract infection (both upper and lower), which may be caused by fungi. Stool culture is important for Treatment gastrointestinal infections. Cerebrospinal fluid is cultured in Intravitreal antifungal agents are given. Some cases need cases of suspected meningitis. Other occult sites which must vitrectomy. The underlying disease process must be be explored in a case of endogenous endophthalmitis are bone controlled. The overall visual prognosis is guarded with useful marrow (biopsy to be taken) and liver (biopsy to be taken). vision being retained only when treatment is started early. Molecular biological techniques may be used to detect . Face, Paranasal Sinus, Orbit and Ocular Adnexa The treatment is by vitrectomy with intravitreal fungal The usual presentation in these organs is a fungal cellulitis. antibiotics like Amphotericin B, which gives encouraging This can be very difficult to treat and may cause death if not (22-24) results only when performed on time. The prognosis is always treated properly. Immunocompromised status due to guarded as most eyes become phthisical with no vision. uncontrolled diabetes mellitus, steroid abuse, drug abuse or HIV infection may cause uncontrollable infection and

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Jemds.com Review Article death.(24,25,26) In diabetic patients, proper management of the CONCLUSION systemic metabolic parameters are very important.(27,28) Fungal ocular infections thus present with diverse clinical Fungal facial cellulitis is a rare entity and unfortunately has pictures in addition to keratomycosis. These disease entities ill-defined treatment guidelines. A high index of clinical are common and are sometimes difficult to treat. If untreated suspicion in appropriate clinical settings is essential for early or poorly treated, many of these conditions can become vision diagnosis and successful outcome. Bodenstein NP et al threatening or even life-threatening. Thus, accurate and rapid mentioned that a black eschar on palate, nose or orbit is a diagnosis and adequate treatment are extremely important in definite clue to the diagnosis. Nontender, periorbital oedema fungal ocular infections. The common aetiological factors is an early feature due to orbital involvement.(29) The initial include presence of uncontrolled diabetes mellitus, use of symptoms of rhinocerebral may be eye pain, over-the-counter steroid preparations, haematologic facial pain or facial numbness followed by onset of malignancies, staying in areas where fungus infection is conjunctival oedema, blurred vision and soft tissue endemic and immunocompromised patients. Many of these swelling.(30) factors are correctable, treatable and preventable. With many Dhiwakar M et al(31) report that perinasal cellulitis or new antifungal agents on the horizon, e.g. posaconazole, paraesthesia is the most common early sign. Periorbital voriconazole, the future of these patients are brighter than oedema, mucopurulent rhinorrhoea and nasal crusting were previous days. Newer treatment modalities and antifungal other early manifestations. The CT scan according to them agents are undergoing trials and there is definite hope that at could be near normal. For immunocompromised patients, least some fungal diseases will be eradicated in the future. therefore a high degree of suspicion is important. Kotzamanoglou K et al(32) highlighted the need to differentiate REFERENCES between fungal orbital cellulitis and bacterial cellulitis as the 1. Chakraborty A, Chatterjee SS, Shivaprakash MR. Overview management is different in two cases and misdiagnosis can of opportunistic fungal infections in India. Nihon Ishinkin cause severe complications. Davis and Stearns.(33) highlighted Gakkai Zasshi 2008;49(3):165-72. the importance of early CT scan in diagnosing sinusitis along 2. Gunasekaran S. Approach to a case of infectious keratitis. with orbital cellulitis, which improved management outcomes. DOS Times 2013;19(1):37. Talmi Y P et al(34) reported that on CT scan, thickening of 3. Klotz SA, Penn CC, Negvesky GJ, et al. 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